Aggressive Male Breast Cancer—Clinical and Therapeutic Aspects Correlated with the Histopathological Examination: A Case Report and Literature Review

Breast cancer is often seen as a disease that occurs in women, but it can also appear in men in a very small percentage, below 1%. Men have a minimal amount of breast tissue compared to women, which has the potential to become malignant in a similar way to women, although much less frequently. A patient presented with advanced local invasion due to the low amount of breast tissue, with the tumor quickly invading the adjacent structures. Histopathological and immunohistochemical examinations have an extremely important role in the pathology of breast cancer. Given that male breast cancer is rare and there are not enough surgeons specializing in breast surgery in our country, there is a lack of experience in the management and early diagnosis of this type of cancer, which will be highlighted in this article.


Introduction
Male breast cancer (MBC) is a rare disease, representing less than 1% of all breast cancers worldwide and approximately 1% of cancers that occur in men [1,2].
Because MBC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female breast cancer (BC) patients [3].
The risk factors are also different for men compared to women.Most affected men do not have associated risk factors.However, some hormonal, genetic and environmental factors have been involved in pathogenesis [4].MBC is more likely to occur in the case of a BRCA2 mutation, unlike female BC, which is more likely to occur in the case of a BRCA1 mutation [5].Also, another known risk factor for men is low androgenic status; respectively, alteration of hormonal balance with excessive stimulation of estrogen was associated with an increased risk of BC [6,7].This may occur in some testicular abnormalities (undescended testis, orchitis), congenital inguinal hernia, infertility, or orchiectomy [8,9].
The risk of MBC increases with age, compared to women whose rate depends on the usual age of menopause; this supports the hypothesis that the midlife change in the rate of increase with age in women is due to the reduction in ovarian hormone production at menopause [10].
Invasive carcinoma of no special type (NST) is the most common MBC [11].Histologic types of ductal origin occur relatively more frequently in men than in women, reflecting the absence of lobular structures in the normal male breast; those of lobular origin are very uncommon in men [10,12].
Although significant efforts have been made to increase awareness of female BC for screening, diagnosis and treatment options, research into MBC has been limited.The management in terms of investigations and treatment options for MBC has been mainly based on the adoption of practices developed to treat female patients with BC [13].

Case Presentation
A 72-year-old male, with no significant familial history, noticed the presence of a tumor in his right breast 1 year ago; initially painless, it became bigger within 6 months and painful with erythematous peritumoral skin.He sought medical attention at a private clinic in January 2022, where they performed an incisional biopsy of the right breast tumor, with the histopathological (HP) examination showing an extended area of invasive lobular carcinoma to the edges of the fragment with areas of ductal carcinoma of low grade in situ and on areas of infiltrative breast carcinoma NST and immunohistochemical (IHC) reactions, indicating invasive breast carcinoma, NST, positive CK7 uniformly in the tumor arrangements, negative CK20, positive mammaglobin in over 80% of tumor cells, positive E-cadherin uniformly, positive estrogen receptor (ER), positive progesterone receptor (PR), Ki67: 56%, and negative HER2.
The patient received four cycles of neoadjuvant epirubicin + cyclophosphamide and four cycles of docetaxel (Figure 1) between March and September 2022 and was hospitalized in the 3rd Surgery Clinic, Emergency County Hospital, Craiova, Romania, in September 2022 for the presence of a tumor in the central quadrant of the right breast, with the presence of local pain, nipple retraction and erythematous periareolar skin.The patient had a partial response to chemotherapy, which is why he was proposed for surgical removal.The inspection revealed that the right mammary gland was found to be slightly enlarged, and the right prepectoral area was tumoral infiltrated of approximately 15/12 cm, with brown overlying skin, without pathological secretions (Figure 2).On palpation, at the level of the right mammary gland, the area of induration can be detected at the level of the central and supero-external quadrants, with the presence of an obvious tumor mass in the central quadrant, increased consistency, adhesion to the deep and superficial planes and without pathological discharge when the nipple is expressed.The right axilla had multiple lymph nodes with diameters between 1 and 2 cm, hard and adherent to the deep and superficial planes.The left breast was found clinically normal.The left axilla with multiple lymph nodes had diameters between 1 and 2 cm, mobile on the deep and superficial planes.Supraclavicular adenopathies were not detected.Ultrasound (US) of the right breast revealed skin with lymphatic edema, thickened by 0.5 cm, with a retracted muriform nipple; heterogeneous glandular tissue, difficult to delimit from the superficial muscular fascia; a polynodular structure and numerous confluent hypoechoic nodules with a diameter between 0.23 and 0.56 cm, located Ultrasound (US) of the right breast revealed skin with lymphatic edema, thickened by 0.5 cm, with a retracted muriform nipple; heterogeneous glandular tissue, difficult to delimit from the superficial muscular fascia; a polynodular structure and numerous confluent hypoechoic nodules with a diameter between 0.23 and 0.56 cm, located predominantly in the central and supero-external quadrants.In the right axilla region, hypoechoic nodules were found and were well delimited and vascularized, with sizes between 1.38 cm and 2.1 cm; in the left axilla, multiple nodules were also found between 0.88 and 2.27 cm, with the same characteristics.
A computed tomography (CT) scan of the chest, abdomen and pelvis revealed, at the level of the right mammary gland, a tissue mass of 30/7 mm, centrally located and tangential to a subcutaneous thickening with a maximum thickness of 4.5 mm, nonspecific infracentimetric nodes in the lower right paratracheal of 13/9 mm, para-aortic adenopathy with a maximum size of 9/7 mm, and a lower left paratracheal node of 9/6 mm.Without the imagistic appearance of bone, lung or liver metastases.
The usual blood tests collected (complete blood count, coagulation profile, urea, creatinine, transaminases, bilirubin test, electrolyte test and tumor markers) were within normal limits, with the exception of the tumor marker CA 15-3, which had a value of 56.01 U/mL.
After the usual preoperatory preparation, surgery was performed, and in the subareolar region, the apparent invasion of the pectoralis major muscle was found, and its partial resection was performed (Figure 3).There were also multiple adenopathic blocks that encased the axillary vein.The dissection of the axillary nodes was difficult due to adhesions to the axillary vein (Figure 4).The lesion evaluation imposed the performance of a right mastectomy with level I and II axillary lymphadenectomy and level III axillary sampling (Figures 4 and 5).Three split skin flaps harvested from the thighs bilaterally were used for the closure of the skin's defect in the same operation (Figure 6).
tial to a subcutaneous thickening with a maximum thickness of 4.5 mm, nonspecific infra centimetric nodes in the lower right paratracheal of 13/9 mm, para-aortic adenopathy wit a maximum size of 9/7 mm, and a lower left paratracheal node of 9/6 mm.Without th imagistic appearance of bone, lung or liver metastases.
The usual blood tests collected (complete blood count, coagulation profile, urea, cre atinine, transaminases, bilirubin test, electrolyte test and tumor markers) were within nor mal limits, with the exception of the tumor marker CA 15-3, which had a value of 56.0 U/mL.
After the usual preoperatory preparation, surgery was performed, and in the subare olar region, the apparent invasion of the pectoralis major muscle was found, and its partia resection was performed (Figure 3).There were also multiple adenopathic blocks that en cased the axillary vein.The dissection of the axillary nodes was difficult due to adhesion to the axillary vein (Figure 4).The lesion evaluation imposed the performance of a righ mastectomy with level I and II axillary lymphadenectomy and level III axillary samplin (Figures 4 and 5).Three split skin flaps harvested from the thighs bilaterally were use for the closure of the skin's defect in the same operation (Figure 6).For establishing the HP diagnosis, the specimen (Figures 7 and 8) was sent to th Laboratory of Pathological Anatomy.For establishing the HP diagnosis, the specimen (Figures 7 and 8) was sent to the Laboratory of Pathological Anatomy.For establishing the HP diagnosis, the specimen (Figures 7 and 8) was sent to th Laboratory of Pathological Anatomy.The HP examination of the mastectomy piece-fixed in formalin, included in paraffi and stained with Hematoxylin-Eosin (HE)-revealed infiltrative breast carcinoma wit the most likely infiltrative micropapillary pattern, with areas of tumor necrosis, perineura invasion and numerous tumor emboli present.The resection limits were uninvaded, an all 12 resected lymph nodes showed carcinoma metastasis.The pathological staging wa T2N3a (stage IIIC).
Due to his advanced age and anesthesia and surgery risks, the patient refused to per The HP examination of the mastectomy piece-fixed in formalin, included in paraffin and stained with Hematoxylin-Eosin (HE)-revealed infiltrative breast carcinoma with the most likely infiltrative micropapillary pattern, with areas of tumor necrosis, perineural invasion and numerous tumor emboli present.The resection limits were uninvaded, and all 12 resected lymph nodes showed carcinoma metastasis.The pathological staging was T2N3a (stage IIIC).
Due to his advanced age and anesthesia and surgery risks, the patient refused to perform a mediastinoscopy and core biopsy from the left axilla.
The IHC study showed that the tumor had a general solid pattern with infiltrative elements (Figure 9) and intense apical expression for epithelial membrane antigen (EMA) (Figure 10) and was ER-positive (Figure 11), PR-positive (Figure 12) and HER2-negative (Figure 13).The Ki-67 cellular proliferation index was low, with about 10% of the tumor cells (Figure 14).E-cadherin expression was studied in infiltrative areas as well as in solid areas of the tumor (Figures 15-17).The presence of neural invasion (Figure 18) and emboli at the level of small vessels was highlighted (Figures 19 and 20).The HP and IHC aspects indicate invasive carcinoma NST.After surgery, the patient's local evolution was a favorable one, and they started adjuvant chemotheraphy (Carboplatin + Gemcitabine) in November 2022 as well as radiotherapy (radiation dose of 50 Gy) between December 2022 and January 2023.From After surgery, the patient's local evolution was a favorable one, and they started adjuvant chemotheraphy (Carboplatin + Gemcitabine) in November 2022 as well as radiotherapy (radiation dose of 50 Gy) between December 2022 and January 2023.From January 2023, the patient started treatment with 2.5 mg of Letrozole once a day, two 150 mg tablets of Abemaciclib a day and Zoladex once a month.Surgical evaluation at 2 months (Figure 21) and 9 months (Figure 22) postoperatively showed favorable local evolution.January 2023, the patient started treatment with 2.5 mg of Letrozole once a day, two 150 mg tablets of Abemaciclib a day and Zoladex once a month.Surgical evaluation at 2 months (Figure 21) and 9 months (Figure 22) postoperatively showed favorable local evolution.The CT scan performed 4 months and 9 months after the surgery showed the absence of suspicious lesions as secondary determinations or tumor recurrence.The CT scan performed 4 months and 9 months after the surgery showed the absence of suspicious lesions as secondary determinations or tumor recurrence.

Discussion
For a comprehensive view of MBC, we performed a literature review using PubMed and Google Scholar from 2014 to 2023 using the terms "male" and "breast cancer"; the filters "free full text" and "Aged: 65+ years" and the article type "case report".We found 187 cases from which we excluded articles with insufficient information, cases of breast metastases from another type of cancer and articles that had other topics but had the keywords contained in them.We have extracted 16 cases of MBC, and these cases are described in Tables 1 and 2 for further discussion.In both men and women, BC incidence increases rapidly with age until the fifth decade of life.However, in men, the incidence continues to increase by the seventh decade, while women's rate plateaus by the sixth decade [28].Our patient was diagnosed at an advanced age.Another reason that explains the increase in the incidence in men is due to the lack of awareness about the existence of breast cancer in males.
The initial diagnosis of female BC often occurs at an earlier stage than in MBC, which is the reason why MBC frequently presents with more advanced features of the disease, correlated with lymph node involvement, larger tumor size, and metastases at the time of diagnosis [29,30].Due to the low breast tissue in men, the tumor quickly invades the adjacent structures.Our case presented an advanced local invasion with a nodule at the level of the right mammary gland with a maximum diameter of 3 cm and multiple bilateral axillary, para-aortic and paratracheal adenopathies, without imagistic bone, lung or liver metastases.
Retroareolar lump is the most common clinical sign in MBC, which was the main and first symptom in our patient's case as well, associated with axillary adenopathies, which, according to Cutuli et al., axillary nodal involvement is present in 50-60% of cases [31,32].In contrast, our review detected the presence of axillary adenopathies in 5 out of 16 cases [14][15][16]26,27], respectively, in 31% of cases.
All patients underwent biopsy for diagnostic purposes, either with a core needle in five cases [14][15][16]18,22], fine-needle aspiration in four cases [23][24][25]27], or excisional biopsy in seven cases [17,[19][20][21]26].Given that MBC is rare and there are not enough surgeons specialized in breast surgery in our country, there is a lack of experience in the management and early diagnosis of this type of cancer.Our patient performed an incisional biopsy in a private clinic instead of a core-needle biopsy, which would have ensured an increased comfort of life and would have been diagnosed faster, and the oncological treatment would have started earlier.
The HP and IHC examinations have an extremely important role in the pathology of breast cancer [33].Considering the very aggressive nature of the patient's cancer with the presence of large tumors, multiple adenopathies, perineural invasion and emboli present in the vessels, the histopathological examination of the mastectomy piece suspected the micropapillary pattern, which was later disproved with the IHC examination.Epithelial membrane antigen (EMA) has a positive marking inside the cellular beaches (reversal of the polarity of the marking compared to an infiltrative micropapillary carcinoma that should have been peripheral to the cellular beaches), which helped us exclude the micropapillary pattern.EMA is also correlated with tumor size, tumor grade, progesterone, estrogen receptors and nodal stage [34].
Estrogen receptors are positive in 75-92% of the cases, while progesterone receptors are positive in 54-77%, according to Cutuli et al. [32,35].Our case showed positivity for estrogen and progesterone receptors, as in the vast majority of MBCs.We have also noticed the presence of estrogen receptors (ER) and progesterone receptors (PR) in most cases from the literature review, with no HER2-positive case.
The expression of Ki67 is used as a proliferation marker, and it is an independent prognostic factor for survival rate [36].A higher Ki-67 value (≥25%) was associated with a favorable response to chemotherapy, and his values significantly decreased to 10% after neoadjuvant chemotherapy [37,38].E-cadherin is considered a tumor suppressor, and its loss has been demonstrated in invasive lobular carcinoma [39].In our case, e-cadherin expression was maintained in the infiltrative areas, decreased in a solid area and preserved in another solid area, which demonstrated the heterogeneous character of the tumor.The IHC reactions performed on the biopsied breast tumor showed positivity for both types of receptors and HER2-negative, which are present in the vast majority of MBC [40,41].
Mastectomy combined with axillary lymphadenectomy for MBC is the surgical gold standard treatment and is more commonly performed (70% of all cases) in this type of cancer [42,43].Surgery for locally advanced cancer should be performed in patients with a partial response to chemotherapy and who are hormone-positive to improve their quality of life [44].In our case, mastectomy with axillary lymphadenectomy was performed for palliative purposes, but although the resection limits of the mastectomy piece were uninvaded and all 12 resected lymph nodes showed carcinoma metastasis, the response to adjuvant oncological treatment was favorable, with a control CT scan performed 4 months and 9 months after the surgery within normal limits.A favorable response was also observed with neoadjuvant chemotherapy, with a significant decrease in the Ki67 values from 56% to 10%.Neoadjuvant chemotherapy was received in 3 cases out of 16, respectively, in 18% of the cases from our literature review.
A study conducted among 411 people, men and women, at the Ankara Training And Research Hospital General Surgery Outpatient Clinic in 2021-2022 highlighted the low awareness of MBC in the general population.Only 38.9% of the study participants knew that men can also develop BC.The study noted that women have a higher level of BC awareness than men [45].An important role in the early detection of MBC is played by education campaigns and the introduction of breast screening programs, at least for men with a family history of BC.

Conclusions
MBC is a rare and frequently neglected disease.It is important to understand the biological differences between male and female BC, which is why it is advisable to view them as two separate diseases.Given that MBC is rare, there is a lack of experience in the management and early diagnosis of this type of cancer, and there are also not enough methods of informing the population in our country about the existence of MBC.The treatment of MBC remains a challenge, and the development of therapeutic strategies is necessary.Also, there are not enough surgeons specialized in breast surgery and breast ultrasound in our country.Multidisciplinary collaboration and the early detection of people at risk and of the signs of BC are essential so that the diagnosis takes place as quickly as possible through the correct therapeutic method and sending the patient to a surgeon specialized in breast surgery.The HP and IHC examinations were essential in establishing the therapeutic attitude.Considering the fact that the patient presented at a very advanced stage (IIIC) of the disease, the treatment solution approached in our patient's case led to very good results.

Figure 2 .
Figure 2. Preoperative image of the patient's right breast after chemotherapy, with the presence of nipple retraction and erythematous periareolar skin.

Figure 2 .
Figure 2. Preoperative image of the patient's right breast after chemotherapy, with the presence of nipple retraction and erythematous periareolar skin.

Figure 3 .
Figure 3. Image of pectoralis major muscle after its partial resection and right mastectomy.

Figure 3 . 2 Figure 4 .
Figure 3. Image of pectoralis major muscle after its partial resection and right mastectomy.Medicina 2023, 59, x FOR PEER REVIEW 5 of 2

Figure 4 .
Figure 4. Image of the axilla after lymphadenectomy level I, II and level III axillary sampling.

Figure 4 .
Figure 4. Image of the axilla after lymphadenectomy level I, II and level III axillary sampling.

Figure 5 .
Figure 5. Image of retropectoral dissection and multiple adenopathic blocks that encased the axillar vein.

Figure 6 .
Figure 6.Image of the three split skins used for closure of skin's defect.

Figure 6 .
Figure 6.Image of the three split skins used for closure of skin's defect.

Figure 7 .
Figure 7. Image of the mastectomy piece, covered by skin, with the presence of nipple retractio and axillary adipose tissue.

Figure 7 . 2 Figure 8 .
Figure 7. Image of the mastectomy piece, covered by skin, with the presence of nipple retraction and axillary adipose tissue.Medicina 2023, 59, x FOR PEER REVIEW 7 of 2

Figure 8 .
Figure 8.The posterior face of the resection piece with the presence of a 3 cm pill of the pectoralis major muscle.

Figure 9 .
Figure 9. Image of a general solid pattern of the tumor with some infiltrative elements (HE staining ×20).

Figure 9 .
Figure 9. Image of a general solid pattern of the tumor with some infiltrative elements (HE staining, ×20).

Figure 9 .
Figure 9. Image of a general solid pattern of the tumor with some infiltrative elements (HE staining ×20).

Figure 20 .
Figure 20.The presence of emboli at the level of small vessels (immunolabeling with anti-CD34 antibody, ×20).

Figure 20 .
Figure 20.The presence of emboli at the level of small vessels (immunolabeling with anti-CD34 antibody, ×20).

Figure 21 .
Figure 21.Appearance of the prepectoral area two months postoperatively.Figure 21.Appearance of the prepectoral area two months postoperatively.

Figure 21 .
Figure 21.Appearance of the prepectoral area two months postoperatively.Figure 21.Appearance of the prepectoral area two months postoperatively.

Figure 21 .
Figure 21.Appearance of the prepectoral area two months postoperatively.

Figure 22 .
Figure 22.Appearance of the prepectoral area nine months postoperatively.

Figure 22 .
Figure 22.Appearance of the prepectoral area nine months postoperatively.

Table 1 .
The main preoperative clinical characteristics across the literature reported cases of MBC between 2014 and 2023.

Table 2 .
HP and IHC aspects across reported cases of MBC between 2014 and 2023.